A novel transcript isoform of STING that sequesters cGAMP and dominantly inhibits innate nucleic acid sensing

Nucleic Acids Res. 2018 May 4;46(8):4054-4071. doi: 10.1093/nar/gky186.

Abstract

STING is a core adaptor in innate nucleic acid sensing in mammalian cells, on which different sensing pathways converge to induce type I interferon (IFN) production. Particularly, STING is activated by 2'3'-cGAMP, a cyclic dinucleotide containing mixed phosphodiester linkages and produced by cytoplasmic DNA sensor cGAS. Here, we reported on a novel transcript isoform of STING designated STING-β that dominantly inhibits innate nucleic acid sensing. STING-β without transmembrane domains was widely expressed at low levels in various human tissues and viral induction of STING-β correlated inversely with IFN-β production. The expression of STING-β declined in patients with lupus, in which type I IFNs are commonly overproduced. STING-β suppressed the induction of IFNs, IFN-stimulated genes and other cytokines by various immunostimulatory agents including cyclic dinucleotides, DNA, RNA and viruses, whereas depletion of STING-β showed the opposite effect. STING-β interacted with STING-α and antagonized its antiviral function. STING-β also interacted with TBK1 and prevented it from binding with STING-α, TRIF or other transducers. In addition, STING-β bound to 2'3'-cGAMP and impeded its binding with and activation of STING-α, leading to suppression of IFN-β production. Taken together, STING-β sequesters 2'3'-cGAMP second messenger and other transducer molecules to inhibit innate nucleic acid sensing dominantly.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Cell Line
  • DNA / physiology
  • Humans
  • Interferon Regulatory Factor-3 / metabolism
  • Membrane Proteins / antagonists & inhibitors
  • Membrane Proteins / biosynthesis
  • Membrane Proteins / genetics
  • Membrane Proteins / metabolism*
  • NF-kappa B / metabolism
  • Nucleotides, Cyclic / metabolism*
  • Phosphorylation
  • Protein Isoforms / biosynthesis
  • Protein Isoforms / genetics
  • Protein Isoforms / metabolism
  • Protein-Serine-Threonine Kinases / metabolism
  • Virus Physiological Phenomena

Substances

  • IRF3 protein, human
  • Interferon Regulatory Factor-3
  • Membrane Proteins
  • NF-kappa B
  • Nucleotides, Cyclic
  • Protein Isoforms
  • STING1 protein, human
  • cyclic guanosine monophosphate-adenosine monophosphate
  • DNA
  • Protein-Serine-Threonine Kinases
  • TBK1 protein, human